Carcinoma of the oral cavity, which is the sixth most common cancer in the world, accounts for about four percent of all cancers and about two percent of all cancer deaths (reviewed in Ankathil et al. (1994) Oncol. Rep. 1:1011-1015). Oral squamous cell carcinoma in particular is newly diagnosed in 50,000 Americans and in 500,000 others worldwide each year (Vokes et al. (1993) N. Engl. J. Med. 328:184-94). Approximately half of the patients afflicted will die within five years of diagnosis while surviving patients may be left with severe esthetic and/or functional compromise (Silverman et al. (1990) J. Am Dent. Assoc. 120:495-499).
Squamous cell oral cancer is usually treated with surgery, radiation therapy, or combined modality therapy. Such treatments, however, may cause non-trivial complications such as xerostomia, poor wound healing, major vessel erosion, and increased risk for the delayed development of secondary neoplasms. (Lebovics in Harrison's Principles of Internal Medicine, 13 th Ed. (Isselbacher et al., eds) McGraw-Hill, Inc., New York) pp. 1850-1853). Furthermore, radical surgery may severely compromise both the appearance and functional and communicative abilities of the patient. Chemotherapy is not used as an initial treatment, and its role as an adjunct therapy is disputed (Lebovics, ibid). Thus, better therapeutic methods for treating oral carcinoma in humans are greatly needed.
Several etiological agents are suspected of causing oral cancer. Predisposing factors such as tobacco use and alcohol consumption have been identified, but there are oral cancer patients who have neither smoked not drunk alcohol for whom the cause cannot be established. Some metabolic deficiencies have been incriminated in oral cancer development, but the mechanisms have not been elucidated. Viral associations have been demonstrated, but whether the virus is an etiological agent has yet to be determined.
The majority of human cancers (70-90%), and oral carcinomas in particular, are thought to be caused by chemically-induced mutagenesis from the environment, either directly or indirectly (Boyd et al. (1988) J. Oral. Path. 17:193-201). These mutagens produce point mutations, deletions, insertions or rearrangements which may activate or suppress genes responsible for tumor phenotypes (Boyd et al. (1988) J. Oral. Path. 17:193-201; and Weinberg (1991) Science 254:1138-46). The activation of specific oncogenes including c-erb, DCC, Bi, Ki-ras, Ha-ras, and c-myc has also been demonstrated in oral tumors.
The loss of function of another group of genes, the tumor suppressor genes, is also implicated in carcinogenesis. Active suppressor genes in normal cells are thought to function as negative regulators of a number of growth processes, including recognition and response to growth and differentiation signals, overriding the transforming effects of oncogenes, immunity to tumors, and inhibition of angiogenic activity (see, Moroco et al. (1990) Lab. Invest. 63:298-306).
In the case of head and neck cancers, the role of at least four tumor suppressor genes has been suggested. For example, certain human oral cancer cell lines were found not to contain "deleted in colon cancer" (DCC) mRNAs (Kim et al (1993) Anticancer Res. 13:1405-1414). Some cells lacking the retinoblastoma (RB) tumor suppressor gene were found to lack receptors to, and sensitivity for, TGF-.beta.-mediated differentiation (Kimichi et al. (1988) Science 240:196). Overexpression of a mutant form of p53 tumor suppressor protein encoded by the p53 oncogene, and lack of expression of wild type p53 protein was detected, while down-regulation of E-cadherin was found to be associated with both invasion and metastasis (reviewed in Ankathil et al. (1994) J. Oncol. Rep. 1:1011-1015). Furthermore, somatic cell hybridization studies using oral keratinocytes isolated from the cheek pouch of a hamster model of human oral cancer have also suggested the presence of tumor suppressor genes (see, e.g., Polverini et al. (1988) Carcinogenesis 9:117-22; Rastinejad et al. (1989) Cell 56:345-55; Moroco et al. (1990) Lab. Invest. 63:298-306). It has recently shown, using normal malignant hamster oral keratinocyte hybrids from this model, that acquisition of three transformed phenotypes (angiogenesis, immortality, and anchorage independence) is linked to the loss of several suppressor gene functions (Moroco et al. (1990) Lab. Invest. 63:298-306). These malignant phenotypes can be suppressed using somatic cell hybridization analysis, further linking the loss of suppressor genes to the onset of various transformed phenotypes (see, e.g., Polverini et al. (1988) Carcinogenesis 9:117-22; Rastinejad et al. (1989) Cell 56:345-55; Moroco et al. (1990) Lab. Invest. 63:298-306).